Neural Circuit Disruption in Freely-Behaving models of Alzheimer's Disease.

阿尔茨海默病自由行为模型中的神经回路中断。

• 批准号: 10448669
• 负责人: Stephen N. Gomperts
• 金额: $ 76.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448669
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Anesthesia procedures; Animals; Apolipoprotein E; Behavioral; Body Temperature; Brain; Breeding; Calcium; Cells; Consumption; Dependence; Development; Early Onset Alzheimer Disease; Electrodes; Evaluation; Exploratory Behavior; Failure; Frontotemporal Dementia; Functional disorder; Generations; Genetic; Goals; Hippocampus (Brain); Homeostasis; Human; Image; Image Analysis; Imaging technology; Impairment; Implant; Knock-in; Knowledge; Late Onset Alzheimer Disease; Medial; Microscope; Modeling; Monitor; Multimodal Imaging; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathology; Physiological; Physiology; Research; Risk; Running; Sampling; Series; Sleep; System; TREM2 gene; Techniques; Technology; Time; Viral Vector; adeno-associated viral vector; apolipoprotein E-4; awake; brain cell; genetic risk factor; image registration; indexing; insight; lens; microscopic imaging; model development; mouse model; multiphoton imaging; neural circuit; neurophysiology; new technology; novel; novel therapeutics; overexpression; programs; relating to nervous system; risk variant; serial imaging; sex; tau Proteins; tau aggregation; tau mutation; therapeutic development; tool; two-photon; unpublished works

Background Summary/Abstract Determining how A and tau degrade neural systems function in Alzheimer’s disease remains an essential objective. Although much has been learned from models of early onset Alzheimer’s disease (EOAD), including demonstration of aberrant neuronal activity and calcium overload in anesthetized amyloid models, the generalizability of these observations depends on two major caveats: First, it is not clear how findings under anesthesia extrapolate, particularly as the effects of amyloid and tau appear to depend on behavioral state. Second, it is not clear whether findings in EOAD models will inform understanding of late onset Alzheimer’s disease (LOAD), which is far more common and arises in association with multiple genetic risk factors. To address these issues, we will apply and integrate a series of new technologies. To extend studies to freely behaving animals and determine the behavioral state-dependence of A’s impact on neuronal physiology, we will employ the Inscopix mini-microscope to monitor calcium activity together with concomitant multi-electrode recordings to assess brain oscillations. To extend studies to LOAD, we study and contrast the APP/PS1 model of EOAD with the new hAbeta.ApoE4.Trem2*R47H model of LOAD. This model, which includes knock-in of the humanized APP gene in concert with the strong risk variants APOE (humanized ApoE4) and TREM2*R47H, develops elevated levels of A42 and A40. To evaluate tau’s contribution to neuronal dysfunction and its interactions with A in these amyloid models, we employ an AAV vector that expresses equimolar levels of human tau and GCaMP6f, enabling dynamic calcium imaging in tau-laden cells with the mini-microscope. To evaluate how the development of tau aggregates interacts with amyloid to affect neuronal physiology, we combine mini-microscope imaging of dynamic calcium activity with 2-photon imaging of tangles and plaques. We hypothesize that in both APP/PS1 (to model EOAD) and hAbeta.ApoE4.Trem2*R47H (to model LOAD), A and tau will be associated with behavioral state-dependent changes in neuronal activity, brain oscillations, and calcium overload; that tau’s state-dependent effects will dominate those of A in the EOAD and LOAD models; and that the development of tau aggregates will synergistically interact with amyloid to degrade neuronal activity. Together, these efforts will establish how A and tau impair neural systems function, advancing Alzheimer’s disease modeling and informing therapeutic development.

背景摘要/摘要 确定A和tau如何退化阿尔茨海默病患者的神经系统功能仍然是至关重要的 目标。尽管已经从早发性阿尔茨海默病(Eoad)的模型中学到了很多东西，包括 在麻醉淀粉样蛋白模型中显示异常的神经元活动和钙超载 这些观察结果的概括性取决于两个主要警告：第一，尚不清楚在 麻醉外推，尤其是淀粉样蛋白和tau的影响似乎取决于行为状态。 其次，目前尚不清楚Eoad模型中的发现是否有助于了解迟发性阿尔茨海默氏症 疾病(负荷)，这是更常见的，并与多种遗传风险因素有关。至 针对这些问题，我们将应用和整合一系列新技术。将研究扩展到自由 ‘S对神经生理学影响的行为状态依赖 将使用Inscope ix微型显微镜和伴随的多个电极一起监测钙活动 用来评估大脑振荡的录音。为了将研究扩展到LOAD，我们研究并对比了APP/PS1模型 使用新的hAbet.ApoE4.Trem2*R47H型号的负载。这种模式，其中包括敲入的 人源化APP基因与强风险变异体APOE(人源化ApoE4)和TREM2*R47H一致， A42和A40水平升高。探讨tau在神经元功能障碍中的作用及其机制 与A的相互作用在这些淀粉样蛋白模型中，我们使用AAV载体来表达等摩尔水平的 人类tau和GCaMP6f，使携带tau的细胞能够在微型显微镜下进行动态钙成像。至 评估tau聚集体的发育如何与淀粉样蛋白相互作用影响神经生理学，我们 将动态钙活动的微型显微镜成像与缠结和斑块的双光子成像相结合。我们 假设在APP/PS1(对Eoad建模)和hAbeta.ApoE4.Trem2*R47H(对负载建模)中，A和 Tau将与神经活动的行为状态依赖的变化、脑振荡和 钙超载；在Eoad和Load模型中，tau的状态依赖效应将主导A的效应； Tau聚集体的形成将与淀粉样蛋白协同作用，从而降低神经元的活性。 总之，这些努力将确定A和tau如何损害神经系统功能，从而促进阿尔茨海默氏症 疾病建模和为治疗发展提供信息。